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Prasad S Adusumilli

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 12
    • Now Available
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      MA12.01 - Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions (Now Available) (ID 1773)

      14:00 - 15:30  |  Presenting Author(s): Matthieu Foll  |  Author(s): Nicolas Alcala, Lise Mangiante, Nolwenn Le Stang, Corinne Gustafson, Sandrine Boyault, Francesca Damiola, Karine Alcala, Julien Mazieres, Jean-Yves Blay, Sylvie Lantuejoul, Raphael Bueno, Christopher Caux, Nicolas Girard, James McKay, Francoise Galateau Sallé, Lynnette Fernandez-Cuesta

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a deadly disease. The current histopathologycal classification recognises three major types (epithelioid, biphasic, and sarcomatoid) with different prognosis, but showes high interobserver variability. This classification also has a role in the clinical decision-making although, ultimately, MPM becomes refractory to all conventional treatment modalities, and alternative therapeutic options have been evaluated with limited success.

      Method

      We have performed unsupervised analyses of publicly available RNA-seq data of 284 MPM tumours1,2 with no assumption of discreteness. We have performed an orthogonal validation in a subset of 187 samples, and we have replicated the findings in an independent series of 77 MPM from the French MESOBANK.

      Result

      A continuum of molecular profiles appeared to explain the prognosis of this disease better than discrete models based on the histopathological classification or on expression data. We identified the immune and vascular pathways as major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples; the extrema of this continuum had very specific molecular profiles: a "hot" bad-prognosis profile (median survival of 7 months), with high lymphocyte infiltration, and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile (median survival of 10 months), with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a better-prognosis profile (VEGFR2+/VISTA+, median survival of 36 months), with high expression of the immune checkpoint VISTA and the pro-angiogenic VEGFR2 gene. We selected five genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), which expression was enough to capture the three molecular profiles, to validate the expression of these genes at the protein level by immunohistochemistry on a subset of 187 samples from the discovery cohort, and to replicate the molecular profiles as well as their prognostic value in an independent series of 77 MPMs.

      picture copy.jpg

      Conclusion

      In this study we found that the prognosis of MPM is best explained by a continuous model, which extremes show characteristic molecular profiles with specific expression patterns of genes involved in the angiogenesis and immune response3. These data may inform future classifications of MPM and provides insights that may assist the clinical management of this disease.

      1Bueno et al., Nat Genet 2016; 2Hmeljak et al., Cancer Discov 2018; 3Alcala et al., under review in Cancer Res; NA and LM equally contributed to this work; MF, FGS, and LFC jointly supervised this work

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      MA12.02 - Growth Patterns in Epithelioid Malignant Pleural Mesothelioma: A Clinicopathological Review of 614 Cases Over 15 Years (Now Available) (ID 1595)

      14:00 - 15:30  |  Presenting Author(s): Yu Zhi Zhang  |  Author(s): Cecilia Brambilla, Alexandra Rice, Jan Lukas Robertus, Simon Jordan, Eric Lim, loic Lang-Lazdunski, Sanjay Popat, Miriam F Moffatt, William O.C Cookson, Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Nuclear grading system has been validated as a powerful prognostic tool for epithelioid malignant pleural mesothelioma (MPM) whilst growth patterns had demonstrated prognostic value in earlier studies. We aim to externally validate the previous findings and evaluate the utility of a composite architecture-nuclear grade scoring system.

      Method

      We retrospectively reviewed 614 consecutive cases of epithelioid MPM diagnosed at our institution over a 15-year period. Clinicopathological information including predominant growth pattern (Solid, Tubulo-papillary, Trabecular, Micropapillary, Microcystic, Discohesive, Pleomorphic) and 2-tier nuclear grade were retrieved from an institutional mesothelioma database. The tumours were categorised into High Grade (Solid, Micropapillary, Score=1) and Low Grade (All others, Score=0). A composite score (0-2) was generated based on growth pattern and 2-tier nuclear grade (0-1). Survival analysis was performed using Kaplan-Meier method.

      Result

      Pleomorphic epithelioid MPM was associated with the worst median overall survival (5.4 months), followed by micropapillary- (6.2 months), solid- (10.5 months), microcystic- (15.3 months), discohesive- (16.1 months), trabecular- (17.6 months) and tubulo-papillary- (18.6 months) patterns. The composite scoring system further improved stratification of overall survival based on 2-tier nuclear grade (19.8 vs. 13.4 vs. 8.1 months, p<0.001).

      growth patterns (except cribriform_wdpm).jpg

      composite architecture-ng score v2.jpg

      Conclusion

      Epithelioid MPM growth patterns predicted survival in our cohort. Composite architecture-nuclear grade scoring system further improved prognostic stratification.

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      MA12.03 - PARP Inhibitor Sensitivity Does Not Depend on BAP1 but Is Enhanced by Temozolomide in MGMT Deficient Human Mesothelioma Cells (Now Available) (ID 2492)

      14:00 - 15:30  |  Presenting Author(s): Raffit Hassan  |  Author(s): Daniel Rathkey, Manakamana Khanal, Junko Murai, Jingli Zhang, Qun Jiang, Betsy Morrow, Christine Evans, Raj Chari, Manjistha Sengupta, Anish Thomas, Yves Pommier

      • Abstract
      • Presentation
      • Slides

      Background

      BRCA1 associated protein 1 (BAP1), a nuclear deubiquitinase involved in DNA double-strand (DSB) break repair by homologous recombination (HR), is frequently mutated in mesotheliomas. Because poly (ADP-ribose) polymerase inhibitors (PARPIs) target PARP1 and PARP2 and induce synthetic lethality in BRCA1/2 mutant cancers deficient in HR, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesotheliomas.

      Method

      Ten patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression and function. Cellular sensitivity to two clinical PARPIs, olaparib and talazoparib were tested as single agents, and in combination with temozolomide. BAP1-deleted mesothelioma cellular models were generated by CRISPR/Cas9 and assessed for sensitivity to PARPIs. Because Schlafen 11 (SLFN11) and O6-methylguanine methyltransferase (MGMT) also drive response to temozolomide and PARPIs, we tested their expression and relationship with drug response.

      Result

      BAP1 inactivating mutations were present in eight of ten cell lines, with two harboring homozygous deletion. Cell lines exhibiting BAP1 expression also showed deubiquitinase activity (DUB). IC50 of olaparib and talazoparib plot classified them into sensitive or resistant population irrespective of BAP1 status (Figure 1). Although BAP1 knockout led to the loss of DUB activity, it did not increase the sensitivity of the cell ines to PARPI. Interestingly, cellular sensitivity to PARPI was increased by temozolomide in MGMT-negative and SLFN11-positive cell lines (Table 1).

      figure 1.jpg

      Figure 1. IC50 of olaparib vs talazoparib – based plot shows a separation of sensitive (red oval) and resistant (blue oval) cell line clusters independent of BAP1 activity.

      table 1.jpg

      Table 1. Summary reflecting combination study between talazoparib and temozolomide in different cell lines having varying MGMT and SLFN11 expression status.

      Conclusion

      BAP1 status does not determine cellular sensitivity to PARPIs in patient-derived mesothelioma cell lines. In MGMT-deficient and SLFN11-positive cells, combination of PARPI and temozolomide is synergistic.

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      MA12.04 - Discussant - MA12.01, MA12.02, MA12.03 (Now Available) (ID 3771)

      14:00 - 15:30  |  Presenting Author(s): Erik Thunnissen

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA12.05 - Genomic Analysis of Long Term Malignant Pleura Mesothelioma Patients Treated with Palliative Chemotherapy (Now Available) (ID 2750)

      14:00 - 15:30  |  Presenting Author(s): Andrea Bille  |  Author(s): Federica Torricelli, Alka Saxena, Rosamond Nuamah, Michael Neat, Leanne Harling, Wen Ng, James Spicer, Alessia Ciarrocchi

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is an aggressive tumor related to asbestos exposure with a median survival of 9 months from diagnosis. The aim of this study was to evaluate correlation between genetic mutations and survival in patients who received only palliative chemotherapy.

      Method

      From 2005 to 2015, 720 patients underwent a surgical pleural biopsy and were diagnosed with malignant pleural mesothelioma. Among these, 27 patients survived longer than 30 months (long survival) from diagnosis and 113 survived less than 30 months. The pleural biopsy of the long term survival patients were reviewed and 12 FFPE samples were considered suitable and matched with 12 FFPE biopsy samples from patients who survived less than 12 months.

      Result

      The DNA of 24 patients was sequenced. One sample did not reach quality to be further considered and was excluded. The mean age of total population was 71.6±8.8 and 15 patients were males (table 1). Eleven patients had a mean overall survival of 5.5 months while 12 patients lived more than 30 months. The mutational analysis identified a total of 428 alterations of which 148, classified as somatic and functional, were further considered. Among these, 85% were missense variants, 8% were variants causing a stop gain, 6% were splice variants. UQCRC1 was significantly associated with a reduced survival of MPM patients (p=0.027); figure 1. Positive trend of correlation was observed between mutations in ACTR1 and CUL1 and short MPM survival. By contrast, no significant correlation was observed between gene mutations and long survival.

      Figure 1.

      figure 1 updated.jpg

      Table 1. patient characteristics.

      Variable

      Long survival

      n=12 (%)

      Short Survival

      n=11 (%)

      P value
      Age (median) 67 72 0.216
      Sex 0.193
      Female 6 (50) 2 (18.2)
      Male 6 (50) 9 (81.8)
      Side 0.684
      Right 7 (58.3) 5 (45.5)
      Left 5 (41.7) 6 (54.5)

      Conclusion

      This is the first study that focusing on MPM patients not suitable for multimodality treatment investigated differences in mutational profile between short and long survivors. Our results suggest a possible role of mitochondria metabolism in mesothelioma aggressiveness.

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      MA12.06 - Patient-Derived Organotypic Tumor Spheroids (PDOTS) Facilitate Therapeutic Screening for Malignant Pleural Mesothelioma (Now Available) (ID 2561)

      14:00 - 15:30  |  Presenting Author(s): Raphael Bueno  |  Author(s): Dalia Larios, Elena Ivanova, Amir Aref, Andrew Portell, Assunta De Rienzo, David Barbie, Cloud P Paweletz

      • Abstract
      • Presentation
      • Slides

      Background

      While genotype directed therapies are an essential aspect of personalized medicine in non-small cell lung cancer (NSCLC), this modality is not currently an option in mesothelioma. Instead there is a need for improved functional testing via predictive platforms that can help identify the susceptibility of patient tumors to drug therapies. Here, we demonstrate the use of a novel ex vivo functional system utilizing 3D microfluidic culture and patient-derived organotypic tumor spheroids (PDOTS) as a platform to study the tumor microenvironment and predict tumor responses to treatment in mesothelioma.

      Method

      We evaluated 31 mesothelioma patient specimens under an IRB approved protocol. PDOTS of mesothelioma were generated as previously described (Larios et al. AACR. 2017; Jenkins et al. Cancer Discovery. 2017). Samples were treated with standard chemotherapy (pemetrexed and cisplatin combined) as well as immunotherapy (ipilimumab and pembrolizumab combined) and live/dead quantification was conducted using dual labeling de-convolution fluorescence microscopy. Positive responses ex vivo included samples with significant cell death to control while positive in vivo responses were based on radiologic lack of tumor recurrence using the response evaluation criteria in solid tumors (RECIST, version 1.1) to assess for disease progression.

      Result

      We found that in treatment naïve specimens prolonged ischemic times were associated with decreased tissue viability (ischemia >25 minutes resulted in decrease of live cells from an average of 81% to 56%), lower tumor yield (< 50% tumor content), and decreased generation of spheroids (< 20 spheroids/well). Specimens with prior treatment were consistently associated with low tissue viability irrespective of ischemic times. Of the 31 specimens studied, 10 samples met viability and tumor content standards to undergo further treatment with standard chemotherapy and immunotherapy, and 5 of those samples were tracked to available patient-treatment response data. Ultimately, comparison of ex vivo and in vivo treatment responses demonstrated that 4 of 5 samples treated with standard chemotherapy had concordant responses to those of patients who received the same or similar post-operative therapy. Notably, our discordant sample exhibited large variation in standard deviations due to technical variability.

      Conclusion

      Here we demonstrate that analysis of ex vivo mesothelioma tissue correlates to in vivo responses. These results suggest that PDOTS can serve as a predictive platform for therapies. Further work streamlining human tissue collection and optimizing factors that affect formation of PDOTS prior to ex vivo treatment analysis should be further investigated.

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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Presenting Author(s): Ania Alay  |  Author(s): David Cordero, Elisabeth Aliagas, S Hijazo-Pechero, Victor Moreno, Ramon Palmero Sánchez, Jose Carlos Ruffinelli, Ricard Ramos, Ivan Macia, Xavier Solé, Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.

      Method

      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.

      Result

      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).

      kaplanmeier_immunegroups.png

      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.

      Conclusion

      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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      MA12.08 - Discussant - MA12.05, MA12.06, MA12.07 (Now Available) (ID 3772)

      14:00 - 15:30  |  Presenting Author(s): Ying Liang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA12.09 - Checkpoint Inhibitors Synergize with Dendritic Cell-Therapy in Pre-Clinical Models and Mesothelioma Patients (Now Available) (ID 2425)

      14:00 - 15:30  |  Presenting Author(s): Robert anton Belderbos  |  Author(s): Floris Dammeijer, Mandy Gulijk, melanie Lukkes, Daphne Dumoulin, Robin Cornelissen, Joachim G.J.V. Aerts

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a lethal, treatment resistant neoplasm. Checkpoint inhibitors (CI) have shown promising clinical effects in a minority of patients. It is hypothesized that low response rates to CI are correlated to low numbers of tumor-infiltrating T-cells in MPM patients. Dendritic cell (DC) therapy instigates an immune response and activates tumor-specific T-cells. DC therapy has proven to be effective in pre-clinical models and in a subset of MPM patients. Upregulation of PD-L1 and PD-1 co-inhibitory checkpoints may suppress DC-therapy induced anti-tumor immune response and limit clinical efficacy. To investigate this, we conducted a preclinical and clinical study to evaluate the clinical and immunological effects of DC therapy combined with CI.

      Method

      Immune competent CBA/J mice were orthotopically injected with a syngeneic mesothelioma cell line. Mice were treated with DC-therapy alone or in combination anti-PD-L1 antibodies at high tumor load when DC-monotherapy was found to be ineffective. Peripheral blood and tumors were obtained for flow cytometric analysis and survival was monitored.
      In a clinical setting, nine patients that received DC therapy were sequentially treated with CI. Progression free survival (PFS) was determined from start of CI, using the modified RECIST criteria.

      Result

      Tumors of mice treated with DC-therapy exhibited a three-fold increase in CD8+ T-cell infiltration which was paralleled by heightened expression of PD-L1 on tumor cells (r2=0.69, p=0.0015). Whereas both anti-PD-L1 and DC-monotherapies were ineffective in prolonging survival in our model, combination immunotherapy did (median OS: 24 vs 35 days, p=0.0063). Immune monitoring analyses demonstrated a synergistic increase in proliferation and activation of circulating T-cell following combination therapy. In the clinical trial 3 patients had partial response, 5 patients had stable disease and 1 patient had progressive disease. Median PFS was 5,2 months and median OS was 17,5 months. Currently 3 patients are still alive and two patients are still progression free. There were no grade 3/4 adverse events. PD-L1 expression in tumor biopsies was increased after DC therapy in two of the three responders to CI.

      Conclusion

      In a murine model the synergy between DC therapy and CI was proven and efficacy was driven by activation of CD4+ and CD8+ positive cells. In humans, CI after DC therapy is safe and feasible. Disease control was seen in 8 out of 9 patients treated with CI after DC therapy. DC therapy induces tumor-specific CD8+ T-cell proliferation which is correlated to PD-L1 expression on tumor cells and possibly synergizes with CI treatment.

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      MA12.10 - Novel Germline Mutations in DNA-Damage Repair and DNA Replication Identified in Patients with Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 1419)

      14:00 - 15:30  |  Presenting Author(s): Robin Guo  |  Author(s): Mariel Duboff, Mark G. Kris, Marc Ladanyi, Diana Mandelker, Marjorie Zauderer

      • Abstract
      • Presentation
      • Slides

      Background

      Recent efforts to characterize the germline genetic landscape of MPM have uncovered a surprising prevalence of pathogenic variants in DNA-damage sensing and repair genes. Increasingly, next-generation sequencing has helped bring new insight into critical mutations or pathways involved in the development of MPM. Additionally, observations from these studies could direct new screening, prevention, and therapeutic approaches for patients and families.

      Method

      With IRB approval, we performed deidentified analysis on 87 additional cancer-predisposing genes on our NGS platform among patients with MPM previously consented to a BAP1 germline testing protocol. Additionally, germline variants in an additional 380 genes associated with somatic alterations in cancer, but not associated with hereditary cancer predisposition, were screened for loss of function variant or pathogenic entries in ClinVar. All variants were reviewed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus guidelines. Founder mutations were excluded. Clinicopathologic information was also collected. Comparisons were done using Fisher’s exact test. P values <0.05 were considered significant.

      Result

      Of 88 patients with MPM analyzed, 11% (10/88) had pathogenic variants. Clinical characteristics such as age, sex, histology, and self-reported asbestos exposure, were similar between patients with and without pathogenic variants (Table 1). Pathogenic variants previously unreported in mesothelioma were identified: MSH3 1/88 (1%; 95% CI: 0-7%), BARD1 1/88 (1%; 95% CI: 0-7%), and RECQL4 2/88 (2%; 95% CI: 0-8%). We also identified pathogenic variants previously associated with mesothelioma: BAP1 in 3/88 (3%; 95% CI: 1-10%), BRCA2 1/88 (1%; 95% CI: 0-7%), and MRE11A 1/88 (1%; 95% CI: 0-7%). One patient had a potentially pathogenic alteration in SHQ1, which has not been associated with a heightened susceptibility to cancer. Patients with germline pathogenic variants were more likely to have more than 2 first-degree family members with cancer compared to those without germline mutations (40% vs 13%; p = 0.049).

      Conclusion

      While the overall incidence of germline mutations identified is similar to prior reports, we identified germline pathogenic alterations in three DNA damage repair and replication genes not previously reported in mesothelioma. Furthermore, we describe a novel germline alteration in SHQ1, which has not been reported with hereditary cancer predisposition. Whether these variants increase the risk of mesothelioma is still under investigation, but given the high rate of germline pathogenic variant in individuals with pleural mesothelioma, germline testing for hereditary cancer susceptibility should be considered in all patients with MPM.

      wclc2019.mesobap1.table-min.jpg

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      MA12.11 - Anti-Tumor Efficacy of Mesothelin Targeted Immunotoxin LMB-100 Plus Pembrolizumab in Mesothelioma Patients and Mouse Models (Now Available) (ID 2316)

      14:00 - 15:30  |  Presenting Author(s): Raffit Hassan  |  Author(s): Qun Jiang, Azam Ghafoor, Daniel Rathkey, Idrees Mian, Jingli Zhang, Betsy Morrow, Ira Pastan

      • Abstract
      • Presentation
      • Slides

      Background

      LMB-100 is an immunotoxin targeting mesothelin (MSLN) that is highly expressed in malignant mesothelioma and lung adenocarcinoma. Given the clinical efficacy of immune checkpoint inhibitors in these cancers, we aimed to evaluate if LMB-100 in combination with αPD-1 antibody will result in greater anti-tumor efficacy.

      Method

      Patients who were treated on a phase I clinical trial of LMB-100 and then received pembrolizumab were evaluated for anti-tumor response and overall survival. We also evaluated LMB-100/αPD-1 combination efficacy in humanized mouse model transplanted with the tumor cells derived from the mesothelioma patient who achieved complete response and healthy donor’s PBMCs. Immune gene expression in pre- and post- LMB-100-treated mesothelioma patient tumor biopsies was detected with NanoString. To further understand the mechanisms of anti-tumor efficacy of LMB-100 plus αPD-1 therapy,we established a human MSLN expressing lung adenocarcinoma syngeneic mouse model with mouse lung adenocarcinoma cell line 531LN2 stably transfected with a vector encoding hMSLN. Using NanoString gene expression assay and flow cytometry, we analyzed drug induced cancer immune responses in 531LN2-hMSLN tumors. Finally, to understand the role of CD8+ T cells in the anti-tumor effects, we depleted CD8+ T cells in LMB-100 plus anti-PD-1 treated 531LN2-hMSLN bearing mice.

      Result

      Nine mesothelioma patients received pembrolizumab, off-protocol, within 3-4 weeks post LMB-100 treatment. Two patients had disease progression before they could be evaluated for tumor response. Out of the 7 patients who were evaluable for response, 4 had durable objective tumor response including 1 complete and 3 partial responses with progression free survival of 104.3+, 49.6, 49.2 and 37.7 weeks. The overall survival of patients with response was 30.2+, 27.7, 23.8+, and 13.8 months from the start of LMB-100 treatments. The immune cell type signature scores including CD45+, CD8+ T cells, exhausted CD8+ T cells, dendritic cells and macrophages were increased in 4 of 6 patients post LMB-100 treatments. The enhanced anti-tumor effects with LMB-100/αPD1 combination were also observed in the PBMC humanized mouse model transplanted with the tumor cells derived the patient with complete response. In the 531LN2-hMSLN mouse syngeneic model, tumor growth was significantly inhibited by LMB-100/αPD-1 treatments than either monotherapy and overall survival was improved in the combination treated mice. The median tumor volume was 865mm3, 420mm3, 277mm3, and 65mm3 in untreated, LMB-100-treated, αPD-1-treated, and combination treated groups respectively on day 34 post tumor inoculation (p<0.001). We observed increased expression of genes related to CD8+T cells and antigen presentation in tumors treated with LMB-100/αPD-1 compared to either agent alone. Flow cytometry confirmed the CD8+T cells increase in LMB-100 /αPD-1 treated 531LN2-hMSLN tumor. Depletion of CD8+T cells significantly negated the anti-tumor benefits in LMB-100/αPD-1-treated mice.

      Conclusion

      Pembrolizumab following LMB-100 is associated with durable tumor response in mesothelioma patients as well as pre-clinical models of mesothelioma and lung cancer. This combination is currently being evaluated in a prospective clinical trial in patients with mesothelioma (clinicaltrials.gov # NCT03644550).

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      MA12.12 - Discussant - MA12.09, MA12.10, MA12.11 (Now Available) (ID 3773)

      14:00 - 15:30  |  Presenting Author(s): Steven Belinsky

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ES12 - Lung Cancer Pathology in the Age of Genomics (ID 15)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      ES12.05 - Impact of STAS in Lung Cancer Staging (Now Available) (ID 3222)

      15:15 - 16:45  |  Author(s): Prasad S Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract

      Spread through air spaces (STAS) is an established histologic marker of poor prognosis found in 15-60% of lung cancers. The association with poor prognosis is supported by data from over 3500 patients from multiple multidisciplinary investigative groups worldwide. This prognostic significance has been demonstrated in all major types of lung cancer including adenocarcinoma,1 squamous cell carcinoma,2 small cell carcinoma,3 large cell neuroendocrine carcinoma,3, atypical carcinoid3 and pleomorphic carcinoma.4, 5

      As this large volume of clinical data has accumulated some important issues that have arisen. 1) Importance of processing, 2) Role in Staging? 3) Limited resection vs lobectomy and 4) Frozen section.

      Criteria for STAS

      The original definition of STAS by Kadota et al and the 2015 WHO consisted of tumor cells within the first alveolar air spaces in the lung parenchyma beyond the edge of the main tumor. In adenocarcinoma it can occur as one of three morphologic patterns including 1) micropapillary structures within air spaces; 2) solid nests or tumor islands and 3) scattered discohesive single cells.1, 6 In a recent paper we also proposed to require the presence of more than a single STAS cluster.3 The solid nest pattern is characteristic in other lung cancer histologies such as squamous cell carcinoma and neuroendocrine tumors. 3-dimensional studies with serial histologic sectioning and microCT whole block imaging suggest that there may be two mechanisms of spread into the adjacent lung: 1) detachment, migration through air spaces and reattachment with vessel co-option and 2) tumor islands of continuous tumor spread into adjacent air spaces.

      An important component of the diagnostic criteria is the distinction from artifacts: 1) mechanically induced tumor floaters that are randomly situated often at the edge of the tissue section or out of the plane of section; 2) jagged edges of tumor cell clusters suggesting fragmentation or edges of a knife cut during specimen processing; 3) isolated tumor clusters at a distance from the tumor rather than spreading in a continuous manner from the tumor edge and 4) linear strips of cells lifted off alveolar walls.

      Importance of Processing

      To assess for STAS histologic sections need to be taken in such a way to maximize the interface between the tumor and adjacent non-neoplastic lung parenchyma. For example, sections of subpleural tumors that maximize assessment of the visceral pleura or the interface with dense fibrotic scars or post-obstructive organizing are not well suited for assessment of STAS. This applies to both frozen and permanent sections.

      Role of STAS in Staging?

      Although the prognostic significance of STAS, has led some to suggest it might be included as a factor in staging,7, 8 there is insufficient data at this time to make such a recommendation. Tumor size should continue to be measured according to the gross and/or microscopically recognized edge of lung cancers rather than according to the maximum distance of furthest STAS. Although vascular (V) and lymphatic (L) invasion are recognized in TNM staging, only visceral pleural invasion (VPI) is officially incorporated as a T-factor in the 8th Edition. STAS is regarded as a sign of invasion similar to V, L and VPI, however, more data is needed before introducing this as a T-factor for staging.

      Limited resection vs lobectomy

      Evidence is accumulating that indicates an increased risk of recurrence and worse survival associated with STAS positive tumors treated by limited resection compared to lobectomy.5, 9

      Role of Frozen Sections in Assessing STAS

      There is limited data evaluating pathologist’s ability to recognize STAS in frozen section. Eguchi et al found the sensitivity and specificity of frozen section for prediction of STAS were 71% and 92%. respectively and interrater reliability across 5 pathologists was 0.67.9

      Walts AE et al studied frozen section for evaluation of STAS and recommended that current evidence did not warrant frozen section evaluation for STAS.10 However, frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and an 8% negative predictive value. These studies suggest if a pathologist sees STAS on a frozen section there is a 92-100% likelihood it will be present on permanent sections. Both studies were retrospective so attention was not always given to including the tumor edge and adjacent lung. More studies are needed to evaluate the potential role of frozen section in detecting STAS and guiding intraoperative decisions by surgeons.

      REFERENCES

      1. Kadota K, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      2. Lu S, et al. Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 2017;12:223-34.

      3. Aly RG, et al. Spread Through Air Spaces (STAS) Is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung. J Thorac Oncol 2019.

      4. Yokoyama S, et al. Tumor Spread Through Air Spaces Identifies a Distinct Subgroup With Poor Prognosis in Surgically Resected Lung Pleomorphic Carcinoma. Chest 2018;154:838-47.

      5. Liu H, et al. Prognostic Impact of Tumor Spread Through Air Spaces in Non-small Cell Lung Cancers: a Meta-Analysis Including 3564 Patients. Pathol Oncol Res 2019.

      6. Travis WD, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.

      7. Uruga H, et al. Will spread through air spaces be a staging parameter in lung cancer? Journal of thoracic disease 2018;10:593-6.

      8. Dai C, et al. Tumor Spread through Air Spaces Affects the Recurrence and Overall Survival in Patients with Lung Adenocarcinoma >2 to 3 cm. J Thorac Oncol 2017;12:1052-60.

      9. Eguchi T, et al. Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score-Matched Analysis. J Thorac Oncol 2019;14:87-98.

      10. Walts AE, et al. Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces. Arch Pathol Lab Med 2018;142:59-63.

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    MS13 - Immunotherapy for Mesothelioma (ID 76)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MS13.05 - CaR T Cell in Mesothelioma (Now Available) (ID 3516)

      11:30 - 13:00  |  Presenting Author(s): Prasad S Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in hematological malignancies and was approved by FDA for the treatment of leukemia and lymphoma patients. Adotpive cell therapy by use of CARs involves transducing patient's own T lymphocytes with antigen-specific CAR by retro or lenti virus, and infusing back to the patient following Cyclophosphamide preconditioning. This presentation will dicuss the challenges in developing CAR T-cell therapy, progress to date in translation of CAR T-cell therapy for thoracic cancers.

      Advances in understanding thoracic cancers tumor immune microenvironment and successes with checkpoint blockade agents has opened doors to devlop combiantion immunotherapy for thoracic cancer patients. Our laboratory has shown that in the presence of high tumor burden as in patients with metastases, a low-dose of CAR T cells adminsitered in phase I clinical trials can be exhausted. Addition of anti-PD-1 agents can rescue functionally exhausted CAR T cells and prolong their anti-tumor efficacy. Based on this strong rationale, our laboratory has translated mesothelin-targeted CAR T-cell therapy for patients with malignant pleural mesothelioma and demonstrated anti-tumor efficacy in addition to safety in combination with anti-PD-1 agents. The results of the ongoing trials will be discussed.

      While extrinsic anti-PD-1 agent administration requires multiple doses and potential off-tumor side effects, we have developed T-cell intrinsic anti-PD-1 strategies which are in translation. The preclinical and clinical data supporting this upcoming clinical trial will be presented.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.03 - Clinical Rationale and Preclinical Evidence for Chimeric Antigen Receptor (CAR) T Cell Therapy Clinical Trial in KRAS-Mutant Lung Cancer (ID 3075)

      11:30 - 13:00  |  Author(s): Prasad S Adusumilli

      • Abstract
      • Slides

      Background

      Chimeric antigen receptor (CAR) T cells are engineered to express a synthetic receptor that redirects specificity to a tumor-associated antigen (TAA). Mesothelin (MSLN) is a TAA expressed by solid tumors, notably in mesothelioma and lung adenocarcinoma (ADC). Our group clinical trial of MSLN-targeted CAR T cells in mesothelioma demonstrated a favorable safety profile and evidence of antitumor activity. In this study, we evaluated the feasibility and utility of MSLN-targeted CAR T cell therapy in advanced, KRAS-mutant lung ADC.

      Method

      Tissue microarray from stage I-III lung ADC tumors (n=1438) were reviewed by two pathologists, then stained for MSLN expression on cell-surface and cytoplasm. Of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for MSLN expression evaluation. Healthy donor T cells were retrovirally transduced with a MSLN-targeted CAR. In vitro function against lung ADC cell lines with heterogenous MSLN expression resembling human tumors was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumor bioluminescence in mice bearing lung ADC tumors.

      Result

      The incidence of cell-surface MSLN expression was higher in metastases than matched primary tumors (65% vs 38%) and higher in KRAS-mutant than wild type tumors (42% vs 32%). CAR T cells secrete cytokines and lyse lung ADC cell lines in proportion to their cell-surface MSLN expression. No activity against MSLN-very low mesothelial or MSLN-negative lung ADC cell lines was observed. In vivo, a single dose of CAR T cells eradicates established primary and metastatic MSLN-high tumors without evidence of on-target off-tumor toxicity.

      Conclusion

      Therapeutically-relevant cell surface MSLN expression is enriched in a population of KRAS-mutant lung ADC patients with poor prognosis and limited treatment options. MSLN-targeted CAR T cells exhibit antigen-specific and antigen density-dependent cytotoxicity against lung ADC cells in vitro and in vivo with no on-target, off-tumor toxicity to normal tissues. These results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung ADC patients.

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